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Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients.

Akt-dependent FOXO3a cytoplasmic translocation is an important tumorigenic mechanism for escaping from apoptosis in cancer cells. In the present study, we examined whether non-phosphorylatable FOXO3a can inhibit cell growth of various follicular thyroid carcinoma (FTC) cell lines. Adenovirus carrying the FOXO3a-triple mutant (TM) sequence including point mutations at three Akt phosphorylation sites (Ad-FOXO3a-TM) was generated and transduced to the cells to mimic inhibition of Akt/FOXO3a signal. Transduction of Ad-FOXO3a-TM to FTC133 cells induced cell cycle arrest and apoptosis. Injection of Ad-FOXO3a-TM suppressed the growth of xenograft tumors in athymic mice. Consequently, our results indicate that gene therapy based on Ad-FOXO3a-TM has therapeutic potential for FTC.